Korzus Edward
Department of Psychology and Neuroscience Program, University Of California Riverside, 900 University Ave, Riverside, CA, 92521, USA.
Adv Exp Med Biol. 2017;978:39-62. doi: 10.1007/978-3-319-53889-1_3.
Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, and mild to severe mental retardation (Rubinstein and Taybi, Am J Dis Child 105:588-608, 1963, Hennekam et al., Am J Med Genet Suppl 6:56-64, 1990). RSTS is caused by de novo mutations in epigenetics-associated genes, including the cAMP response element-binding protein (CREBBP), the gene-encoding protein referred to as CBP, and the EP300 gene, which encodes the p300 protein, a CBP homologue. Recent studies of the epigenetic mechanisms underlying cognitive functions in mice provide direct evidence for the involvement of nuclear factors (e.g., CBP) in the control of higher cognitive functions. In fact, a role for CBP in higher cognitive function is suggested by the finding that RSTS is caused by heterozygous mutations at the CBP locus (Petrij et al., Nature 376:348-351, 1995). CBP was demonstrated to possess an intrinsic histone acetyltransferase activity (Ogryzko et al., Cell 87:953-959, 1996) that is required for CREB-mediated gene expression (Korzus et al., Science 279:703-707, 1998). The intrinsic protein acetyltransferase activity in CBP might directly destabilize promoter-bound nucleosomes, facilitating the activation of transcription. Due to the complexity of developmental abnormalities and the possible genetic compensation associated with this congenital disorder, however, it is difficult to establish a direct role for CBP in cognitive function in the adult brain. Although aspects of the clinical presentation in RSTS cases have been extensively studied, a spectrum of symptoms found in RSTS patients can be accessed only after birth, and, thus, prenatal genetic tests for this extremely rare genetic disorder are seldom considered. Even though there has been intensive research on the genetic and epigenetic function of the CREBBP gene in rodents, the etiology of this devastating congenital human disorder is largely unknown.
鲁宾斯坦-泰比综合征（RSTS）是一种罕见的人类遗传性疾病，其特征为生长发育和精神运动发育迟缓、大体解剖结构异常以及轻度至重度智力障碍（鲁宾斯坦和泰比，《美国小儿疾病杂志》105:588 - 608，1963年；亨内卡姆等人，《美国医学遗传学杂志增刊》6:56 - 64，1990年）。RSTS由表观遗传相关基因的新生突变引起，这些基因包括环磷酸腺苷反应元件结合蛋白（CREBBP）、编码被称为CBP的蛋白的基因以及EP300基因，EP300基因编码p300蛋白，它是CBP的同源物。最近对小鼠认知功能潜在表观遗传机制的研究为核因子（如CBP）参与高级认知功能的调控提供了直接证据。事实上，RSTS由CBP基因座的杂合突变引起这一发现表明CBP在高级认知功能中发挥作用（佩特里等人，《自然》376:348 - 351，1995年）。已证明CBP具有内在的组蛋白乙酰转移酶活性（奥格里兹科等人，《细胞》87:953 - 959，1996年），这是CREB介导的基因表达所必需的（科尔祖斯等人，《科学》279:703 - 707，1998年）。CBP中的内在蛋白乙酰转移酶活性可能直接破坏与启动子结合的核小体的稳定性，促进转录激活。然而，由于发育异常的复杂性以及与这种先天性疾病相关的可能的基因补偿作用，很难确定CBP在成人大脑中认知功能方面所起的直接作用。尽管对RSTS病例的临床表现方面已进行了广泛研究，但RSTS患者中发现的一系列症状只有在出生后才能观察到，因此很少考虑针对这种极其罕见的遗传性疾病进行产前基因检测。尽管对啮齿动物中CREBBP基因的遗传和表观遗传功能进行了深入研究，但这种严重先天性人类疾病的病因在很大程度上仍不清楚。
